This application is a 371 of PCT/FR99/02196 filed on Sep. 15, 1999.
The present invention relates to a novel process for the preparation of vitamin E. It relates more particularly to a novel process for the condensation of trimethylhydroquinone and isophytol.
It is known, for example according to Japanese Patents No. 60064977, No. 53144574 and No. 53015381, to condense isophytol with trimethylhydroquinone in the presence of a Lewis acid, restricted to zinc chloride, in the presence of an inorganic acid chosen from halogenated acids and polyphosphoric acid in a solvent composed of methylene chloride and acetic acid.
It is also known, from Japanese Patents No. 59190987 and No. 48072168, to condense trimethylhydroquinone with isophytol in the presence of a catalyst based on zinc chloride and of an acid chosen from hydrochloric acid or trichloroacetic acid; the reaction being carried out in a solvent composed of an acetyl ester and in particular of isopropyl acetate.
Finally, it is known, from Japanese patent No. 48072167, to condense isophytol with trimethylhydroquinone under the same conditions as above but removing the water of the reaction as it is formed during the condensation. Japanese Patent No. 6226976, which carries out the reduction of trimethylhydroquinone and the condensation with isophytol in the same solvent as above, that is to say isopropyl acetate, eliminates the presence of water between the two stages so as to avoid the presence of water during the final condensation of trimethylhydroquinone with isophytol.
The present reaction can be represented schematically in the following way: 
in which scheme A represents a halogen atom, a hydroxyl group or an acetoxy group.
It has transpired, entirely surprisingly, that, if it is desired to restrict the consumption of TMHQ to 1 molar eq. with respect to isophytol, the presence of water in the condensation stage has a favourable effect on the reaction, contrary to that suggested by all of this prior art. The water prevents side reactions of TMHQ at the beginning of the running in of isophytol.
Furthermore, it is known, according to Patent EP 0 850 937, that it is possible to condense TMHQ with isophytol in the presence of water provided that a nonpolar solvent, such as an alkane, is used. The maximum amount of water which can be used without harming the reaction yield and without distilling off the water formed during the reaction is limited to 1.5 mol of water per mole of isophytol. Under these conditions, the influence of the amount of zinc chloride used was not studied.
It has transpired that, when the process described previously is carried out, that is to say when the catalysis with zinc chloride was carried out in the absence of water and in a polar solvent, such as esters, there was a significant lose of TMHQ by transesterification with the solvent. The present invention has made it possible to overcome this problem and has made it possible to carry out the condensation of TMHQ with isophytol in a polar solvent of the ester type and in the presence of water.
The present invention thus consists in carrying out the condensation of a phytol with trimethylhydroquinone in a polar solvent of the ester type and in the presence of a Bronsted acid and of a zinc halide, characterized in that the reaction is carried out in the presence of an amount of water of between 0.7 molar eq. and 2 molar eq. with respect to the number of moles of zinc halide and in the presence of an amount of zinc halide of greater than 0.3 molar equivalent with respect to the phytol.
The presence of this amount of water has numerous advantages:
it makes it possible to increase the reaction yield by approximately 4%,
it makes it possible to recycle the zinc halide,
at equivalent stoichiometry for TMHQ and phytol, the presence of water increases the yield,
it prevents the esterification of TMHQ by the solvent.
Furthermore, in the case of solvents from the family of the esters, in contrast with the case of the hydrocarbons disclosed in Patent EP 0 850 937, the presence of water requires the use of amounts of zinc halides of greater than 0.3 molar equivalent with respect to phytol, so as:
to retain a yield  greater than 92%
to accelerate the kinetics of the reaction.
The phytol is chosen from isophytol or a phytyl halide, such as phytyl bromide, phytyl chloride or phytyl acetate.
The reaction is carried out in particular in the presence of a Bronsted acid chosen from hydrochloric acid or sulphuric acid. It is preferable to use hydrochloric acid.
The reaction is carried out in the presence of a polar solvent which makes it possible to dissolve trimethylhydroquinone and the phytol used. Mention may be made, among polar solvents which may be used, of esters and among these of ethyl, propyl, isopropyl, butyl or isobutyl acetate; acetates having a longer chain are not preferred although they can be used; the viscosity of the solvent simply increases with the length of the chain, which is not very favourable to the reaction. Esters of longer organic acids than the acetates can also be used, in particular esters of propionic, butyric or isobutyric, valeric or isovaleric acid, but, as in the case of the acetates, the increase in the length of the chain increases the viscosity of the medium, which is not always favourable to the reaction. It is preferable, among all these esters, to use isopropyl acetate.
The presence of water in the reaction medium, which improves the condensation yield, leads in some cases to the presence of a two-phase system. In this case, it is advantageous to add an organic acid chosen from acetic acid, propionic acid or butyric acid in order to prevent the phases from separating. It is preferable to use the acid corresponding to the ester used as solvent. Thus, when an acetate is used, it is preferable to add acetic acid.
The amount of organic acid added corresponds to approximately 3 to 20 times the amount by weight of water present in the medium.
The catalyst used to promote the condensation is chosen from zinc halides. It is preferable to use zinc chloride. It is advantageous also to use a Bronsted acid chosen from hydrochloric acid or sulphuric acid.
According to a better way of implementing the invention, the catalyst is used according to a ratio of approximately 0.7 to 1.2 equivalents per mole of phytol.
The advantage of using this amount of Lewis acid with respect to the prior art, which uses less thereof, is:
to increase the reaction rate,
to improve the selectivity of the condensation.
The molar ratio of the hydroquinone to the phytol is preferably between 1 and 1.5 and it is highly preferably between 1 and 1.2. The Bronsted acid is preferably used according to a molar amount of between 4% and 16% with respect to the number of moles of phytol.
For a better implementation of the invention, it is preferable to operate at a temperature of between 55xc2x0 C. and 75xc2x0 C.
The xcex1-tocopherol obtained is separated from the reaction medium by liquid/liquid extraction.
The following stage of the process for the preparation of vitamin E, when it is provided in the acetate form, consists in carrying out the acetylation of the xcex1-tocopherol.
This stage is carried out according to a novel method which consists in acetylating the xcex1-tocopherol with acetic anhydride in the absence of any solvent, that is to say neat.
The acetylation is carried out in the presence of a catalyst composed of an inorganic acid chosen from sulphuric acid or phosphoric acid or of an alkaline acetate.
It has been discovered that it is preferable to employ phosphoric acid or sodium acetate as it is possible, with these catalysts, to completely avoid colouring the reaction medium during the acetylation. The tocopheryl acetate obtained is even lighter than the starting tocopherol. It is preferable to use a molar ratio of the acetic anhydride to the tocopherol of between 1 and 1.8. Use if preferably made of 0.7 to 2 molar % of acid as acetylation catalyst when the latter is sulphuric acid, 1 to 2 molar % when the acetylation catalyst is phosphoric acid and 5 to 10 molar % when the acetylation catalyst is sodium acetate.
The present invention also relates to a complete process for the preparation of vitamin E from trimethylbenzoquinone, the entire process being carried out in the same solvent, which is a good solvent for trimethylbenzoquinone, for trimethylhydroquinone and for the phytol. This solvent is in particular a polar solvent, preferably an ester and highly preferably isopropyl acetate.
It consists, in a first stage, in carrying out a hydrogenation of trimethylbenzoquinone with a hydrogenation catalyst, preferably a supported catalyst, chosen from palladium and platinum. It is preferable to use palladium supported on charcoal.
The second stage consists, after filtration so as to remove the catalyst, in carrying out the condensation of the trimethylhydroquinone obtained in the first stage with the phytol under the conditions described above and in particular in the presence of a zinc halide, of a Bronsted acid and of water and very particularly in the presence of zinc chloride, of hydrochloric acid and of water. At the end of the reaction, the catalyst is extracted with water and this aqueous phase is concentrated, in particular from 80 wt % to 91 wt % of ZnCl2, so as to leave at most, including the water from the Bronsted acid, only two moles of water per mole of zinc halide recycled to the second stage of the process.
The organic phase is then preferably concentrated to dryness, so as to remove the reaction solvent and its possible by-products, and then acetylated neat as described above.
The process for the extraction of vitamin E acetate is subsequently carried out conventionally and in a way known to a person skilled in the art. The medium is extracted with a solvent which is immiscible or virtually immiscible with water, then washed with an acid solution, so as to hydrolyse the remaining acetic anhydride, and then washed in alkaline medium, to deacetylate the TMHQ acetates. The aqueous phase comprising the alkaline salt of TMHQ is isolated by a two-phase separation, this phase is acidified and the TMHQ is extracted with the reaction solvent, that is to say the ester, which allows it to be recycled to the condensation stage.